Next-generation antibodies on the verge of therapeutic breakthroughs

Simon Woodward,
Christoph Nabholz,
13 Sep 2012

Antibody treatments have grown exponentially in recent years to make them one of the most important category of drugs on the market. The potential for further development is considerable. Equally, the research and development challenges of bringing new antibodies to lengthy regulatory approval and finally to the market remain considerable. Swiss biotech companies are at the forefront of antibody product development. These have the potential to change the effectiveness of treatments substantially.

As such, they are of interest to re/insurers. Swiss Re hosted a Swiss Biotech Roundtable on 10 July 2012, to discuss this exciting science with some of the leading experts in the field.

Current status in antibody research and therapies

Antibodies are the most successful drugs to recently come through clinical tests. Small molecules have a much higher probability of failure. Antibodies are also very successful in commercial terms, with monoclonal antibodies earning around USD 45 billion globally per year.

Antibodies are not a new technology. In the early days of laboratory development, antibodies were developed in mice, but frequently rejected by the human immune system as a foreign protein. Workarounds were developed replacing mouse sequences to partial human sequence, which results in a lower immunogenicity when administered to patients.

Besides classical monoclonal antibodies, several strategies are pursued to make use of the advantages of antibodies which are mainly high specificity and low off-target activity resulting in a much better safety profile than small molecule drugs. A prominent strategy is to increase potency of antibodies with the use of glycosylation for which several compounds are in clinical development. Furthermore, antibody fragments are also in development which have the advantage that the fragment only binds and neutralizes the target, but does not provoke any immune response in contrast to the full length antibody. In addition, other technologies based on antibodies are in clinical development that include bi-specific antibodies, with bind to two different targets which for instance can physically bring to different cells together like a cancer and an immune active cell.

In terms of clinical development, 62% of trials are targeting cancer, 27% immunological disorders and 11% other conditions. In terms of FDA approved antibodies, over 50% are for immunological disorders, but only 33% to cancer. Most antibodies (from published surveys) block protein-protein interactions (48%). The second largest category is receptor modulators (28%) and cytokine modulators (15%). Proportionally more cytokine molecular targets have been approved.

Approval times are becoming longer for antibodies. It currently takes a little under nine years from the first trials to approval. It is unclear whether this extended time has reached a plateau or whether it is still growing.

One example of a successful chimeric antibody has been Remicade, a cytokine modulator to treat autoimmune diseases. Trials began in 1991. Initially rejected in phase two clinical development for sepsis in 1995, it was finally launched on the market for a different indication (Crohn's disease) in 1998. With the approval for five more indications over the last decade sales took off. They currently stand at around USD 7 billion. The product was launched by Centocor, a relatively large pharmaceutical company – if it had been a biotech company, it probably would have gone bust with the first rejection.

Major pharmaceutical companies have taken over biotech companies in antibody research. There are only a small handful of these companies still trading as independent entities. Current hot research topics within antibody research include fragments (including alternative scaffolds); bi-specific antibodies; and antibody drug conjugates.

Within Switzerland there is currently a cluster of around 188 biotech companies, a number which has grown steadily over recent years. More than 30 companies in Switzerland are developing antibody drugs positioning Switzerland in the forefront of research and development.

The impact of monoclonal antibodies on human health

Scientific discovery alone is not sufficient to advance human health. Technology is also required as is therapeutic opportunity, market access, regulation and commercialisation. This all takes time, and forms the context of drug development.

Evolution of therapeutic antibodies

Serotherapy is more than a hundred years old and was subject of the first Nobel Prize in Physiology or Medicine. It was discovered that horse anti-sera could protect patients from certain bacteria and toxins. Within a few years this discovery was used across the world. It could also cause sera sickness, so has become steadily less common, but is still used to treat diphtheria.

Horse sera was gradually replaced by evolving technology, with monoclonal antibodies first introduced into clinical practice in 1985. In 1990 the failure of antibodies against sepsis and difficulties in antibody manufacture lead to doubts over the future of antibodies; doubts which were beginning to be reversed in 2000 with improvements in manufacturing technique, so that more than 30 antibodies are currently in use.

There are various means to make monoclonal antibodies: humanisation of mouse antibodies, selection from human libraries, immunization of transgenic mice and finally cloning human B cells and plasma cells. Antibodies have many advantages as drugs. They are specific in their targets; they are generally safe; can display different types of effector functions; can be efficiently manufactured and have a very long half live.

The main therapeutic targets for antibodies are cytokines, immune regulation, tumour cells and infectious agents. The main themes are developing human antibodies; finding new and better targets; more broadly neutralising antibodies; improving pharmacokinetics; new and improved effector functions; and biosimilars/biosuperiors.

Antibodies can be engineered to improve their effectiveness. For example, the small binding site of camel antibodies can be used to effectively place the antibody in the deep canyons of some antigens. Additional effector functions include antigens, drugs, toxins and radionuclides. There is also a developing field of alternative domains, such as ankyrin and leucine rich repeats.

The immune system remains a central target for cancer therapy. This may be in the use of antibodies to block inhibitory receptors to help boost T-cell responses to cancer; or the use of bispecific antibodies which retarget T-cells against tumours.

Antibodies and infectious diseases

For the first six to eight months of life new-borns are protected from infectious agents by their mother's antibodies. Humabs, established in 2004 as spin-off from the Institute for Research in Biomedicine, uses two proprietary technologies to isolate the most potent and broadly virus-neutralising antibodies from selected donors, with an efficiency rate of 30-50%. This can be done through the immortalisation of memory B cells and the use of single plasma cell cultures. An antibody that neutralizes all influenza A viruses been discovered with this approach. There were no escape mutants from this antibody.

Humabs is also working on an antibody that can neutralise two major respiratory viruses (RSV, MPV). The results were 5-10 fold more potent than Synagis, a humanized monoclonal antibody currently on the market, again with no escaped mutants. Many other diseases are now being examined, notably rabies, a fatal disease in much of the developing world, hepatitis B and bacterial infections.

Antibody technology can also feed vaccine technology. Complex viruses, such as the cytomegalovirus, may be combated with antibodies. In this case potent neutralizing antibodies led to the identification of a new vaccine candidate.

Future targets for antibody technology will remain the stimulation of the immune system; combating infectious diseases; oncology; and possibly neurodegenerative diseases although proof of concept in this field is still lacking. On the molecular side, development will focus on full human antibodies; broadly neutralising antibodies; improved and novel effector functions; new format antibodies; multispecific antibodies; antibody drug conjugates; vaccine design and vectored immunotherapy.

Next generation antibodies: a big biotech's perspective on conditions for success

Francis Marsland, VP European Corporate Development, Biogen Idec

Antibodies and their derivatives are excellent therapeutic modalities. Five of the top ten selling drugs in 2010 were antibodies, with revenue of USD 34 billion. In 2014 that may rise to around 7 in ten. The total market for monoclonal antibodies is around USD 45 billion. Around 28% of FDA biologic approvals were for monoclonal antibodies and derivatives in 2011.

Biogen Idec's discovery pipeline begins with target selection and hypothesis. Screening assays are undertaken before candidate antibody proteins are developed. Finally the company needs to develop manufacturing cell lines and characterisation packets. To make the process work effectively it takes a village of technical experts. Collaboration has to be highly integrative. Discovery technologies have to be robustly screened and assayed, early physiochemical assessments made, the desired scaffold properties engineered and finally the production platform fit assessment completed. This will ultimately lead to a development sweet spot, preferably within the shortest time possible.

Antibodies are being developed by Biogen Idec with a particular focus on neurological and immunological diseases. In the area of translational medicine and technology, the antibody discovery groups provide assays, screening technologies and other services. Biogen Idec is agnostic as to the source of the antibodies developed. The company recognises the increasing importance of biomarkers in all its development programs and is exploring modalities for the effective delivery of therapeutics across the blood brain barrier.

Biogen Idec foresees the most fruitful antibody development areas in coming years to be: antibodies with tailored effector functions, as reducing or enhancing functions; bispecifics (particularly important in oncology); monovalent antibodies; antibodies with payloads, particularly in oncology; and antibody fragments and alternate scaffolds.

However, for all the potential of antibodies, much will come down to market realities. From a business development perspective, it is a buyer's market currently; there are lots of companies developing antibody technologies; venture capital is hard to find. Good science is essential, but it may not be enough to demonstrate the commercial value proposition of a biotech’s antibody development program. Some therapeutic areas are already very well served. Biosimilars are on the way. This will have a profound effect on profitability in many markets. The era of profitable incrementalism is past. It is necessary to demonstrate clinical differentiation and cost-effectiveness. For high priced therapeutics, including antibodies, the bar has been raised to be first in class or best in class. The challenge of turning scientific innovation into commercial success has never been greater.

Summary of panel discussion

Moderated by Christoph Nabholz, Head Business Development, Swiss Re Centre for Global Dialogue

The panel discussion was informative and wide ranging, focusing on a number of points:

1. Therapeutic opportunity

Monoclonal antibodies have been one of the most important advances in the treatment of cancer over the last three decades. Their ability to selectively target tumour cells has provided substantial advantages over conventional chemotherapy, particularly in terms of reduced toxicity. Monoclonal antibodies have therefore become established as a key therapeutic modality in cancer as well as in a range of other diseases. However, that is far from the end of the story; with ever greater understanding of the pathways that enable cancer cells to develop and grow, new targets are identified and monoclonal antibodies continue to be a thriving area of research and development.

The next generation of antibodies will be defined by science. Antibody research will be targeted at viruses for which no drugs currently exist, for prevention and for chronic infections. The bottleneck will be lack of motivation to go forward without knowing exactly what the target population will be or the area that will be targeted. Research is further being undertaken into the potential of antibodies to work against neurodegenerative diseases.

There may well be innovations in the way antibodies are delivered. Currently all antibodies are injectable; what if antibodies could be developed that could be administered in other ways? For example, it may be possible to administer an antibody through a skin cream. This goes against conventional wisdom, in that skin should protect the body from alien proteins, but new innovations are rendering the development possible.

The discussion explored issues such as the place of monoclonal antibodies alongside small molecules. Combination use of one monoclonal antibody with another, or with a small molecule could offer benefits by targeting multiple pathways at the same time. However, clinical evidence for each combination will need to be gathered. Uncertainties also exist around optimal dosage and duration of therapy. Despite all the advances so far, many areas of unmet clinical need still exist, particularly for cancers where there has been little or no impact on survival, such as pancreatic cancer.

2. Market access and regulation

Research has identified many potential new targets and monoclonal antibodies are being developed against these targets. One of the challenges is the difficulty to predict how well the theoretical mechanism(s) of action will translate to health benefits, such as disease free survival and overall survival. The drug development process, which includes pre-clinical studies followed by phases of clinical development, takes several years and is resource intensive. Only a minority of candidate molecules progress through all the stages of development, and eventually to regulatory approval by the US Food and Drug Administration (FDA) or other similar organisations around the world.

Europe is currently a patchwork. Demonstrating value in one country is very different from another. There may be volume limits, potentially clawbacks, patient limitation or the subjective notion of increase in quality of life years. There is impetus within the European Commission to create a unified approach. However, we are miles away from talking about a European standard for demonstrating clinical value add and/or cost effectiveness. All of this impacts on how profitable pharmaceutical companies will be in the future and demonstrates how risky the development process is.

3. Commercialisation

A number of technically promising antibodies have struggled to make a commercial impact, either because of budgetary restrictions or because of the nature of clinical practice. Drugs with burdensome logistics and handling requirements (eg radio-labelled antibodies) have found themselves restricted to centres and specialists, and may never recover their development costs. It underlines how biotech has to be aware of the realities of clinical practice in bringing new antibodies to the market.

Antibodies are extremely successful as drugs. They are being sold to largely two categories of patient – the severely ill and rich. Biosimilars may help, but will still be comparatively expensive. Can antibodies be extended to less severely ill patients and those with less money? There is a whole new market in the middle of the health pyramid. The main block to this is regulatory standards, which increase costs considerably.

Antibody therapies in oncology have been an advantage, but did not point to any solution. Again, cost plays an issue. Breast cancers have responded favourably to treatment with two antibodies; however, the cost of administering two such antibodies is significant. Clinicians feel a social gap widening, even within Europe.

Companion diagnostics are likely to be an integral part of antibody development. It is essential in the clinical development phase to emphasise to regulators the effectiveness of the drug. It further helps justify a premium price. They will be an essential part of most development programmes. Commercial and economic interests of pharmaceutical companies and timelines of diagnostics are some way apart. However, from the biotech side this is more challenging. For biotech companies, well defined populations are better targets than broad populations that need extensive diagnostics.

Authors

Simon Woodward

Senior Business Development Manager, Swiss Re Centre for Global Dialogue

Simon Woodward is a Senior Business Development Manager within the Swiss Re Centre for Global Dialogue. At the Centre, he is responsible for content development and creation; and working with the Swiss Re Group Advisors. Prior to Swiss Re, Simon worked in the communication department of Zurich-based reinsurer, Converium. Before coming to Switzerland, he worked in political and economic risk analysis and developing sovereign credit risk models. Simon graduated from Birmingham University, with post graduate qualifications from St Anthony's College, Oxford, Birkbeck and Open Universities.

Christoph Nabholz

Head Business Development, Swiss Re Centre for Global Dialogue

Christoph Nabholz is Head of Business Development at the Swiss Re Centre for Global Dialogue and additionally serves as Research & Development Manager to Swiss Re’s Life & Health Division.

As Head of Business Development he is responsible for the content of high-profile industry events held at the Centre for Global Dialogue, Swiss Re’s premier conference facility. With his background in genetics he actively supports Swiss Re’s research on and development activities in medical trends and longevity.

Before joining the Centre, Mr Nabolz was Strategic Research Manager in Global Life & Health Underwriting and served as Swiss Re’s Global Genetics Consultant.

Prior to joining Swiss Re, he was a postdoctoral fellow in genomics and functional genetics with Prof. Tom Maniatis at Harvard University. He received a diploma in biochemistry from the University of Basel, Switzerland, and a Ph.D. with honours in molecular genetics from the University of Freiburg, Switzerland.

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